Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].CC(C)([O-])C.[K+].[CH2:34]([O:36][CH2:37]Cl)[CH3:35]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:8])=[O:9])=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]([CH2:37][O:36][CH2:34][CH3:35])[C:3]=1[C:24]([F:25])([F:26])[F:27]
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Reactant: CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOCn1c(-c2ccc(Cl)cc2)c(S(=O)(=O)c2ccc(Cl)cc2)c(Br)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A solution of 3-bromo-5-(p-chlorophenyl)-4-[(p-chlorophenyl)sulfonyl]-2-(trifluoromethyl)pyrrole (0.92 g, 1.84 mmol) and potassium tert-butoxide (0.26 g, 2.21 mmol) in tetrahydrofuran is stirred at room temperature for 5 minutes, treated with a solution of chloromethyl ethyl ether (0.21 g, 2.21 mmol) in tetrahydrofuran, stirred at room temperature overnight, diluted with ethyl acetate, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a white solid (0.98 g, mp 107°-112° C.).
Reaction SMILES: [C:1]([C:3]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]3[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([CH3:22])[N:14]=3)[CH2:9][CH2:8]2)[O:5][N:4]=1)#[CH:2].[CH2:23]([Li])CCC.CCCCCC.CI>C1COCC1>[CH3:22][C:15]1[N:14]=[C:13]([N:10]2[CH2:11][CH2:12][C:6]3([O:5][N:4]=[C:3]([C:1]#[C:2][CH3:23])[CH2:7]3)[CH2:8][CH2:9]2)[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=1
Reactant: [Li]CCCC
Reactant: C#CC1=NOC2(CCN(c3nc(C)ccc3[N+](=O)[O-])CC2)C1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CC#CC1=NOC2(CCN(c3nc(C)ccc3[N+](=O)[O-])CC2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
Into a solution of Compound 11a (25 mg, 0.83 mmol) in THF (1.26 mL) kept under stirring at −78° C., Butyllithium in Hexane (2.5 M, 0.04 mL, 0.1 mmol) is added dropwise. After 30 min., methyl iodide (6.22 μL, 0.1 mmol) was added. The cold bath was removed and the orange solution was allowed to reach r.t. After overnight resting, it was quenched with a saturated aqueous NH4Cl sol., extracted with EtOAc, washed with H2O, dried on Na2SO4 and the solvent was evaporated to dryness in vacuo. The crude the crude was purified by automated flash liquid chromatography (Horizon®TM-Biotage) (Petroleum Ether-EtOAc gradient from 95:5 to 6:4) giving 6 mg of the title compound. Yield: 22.9%.
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][O:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[C:27](=[O:29])=[O:28].C(O)C.O>CCOCC.[Na].[Hg]>[CH3:1][CH:2]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][O:5][C:6]1[S:7][C:8]([C:27]([OH:29])=[O:28])=[CH:9][CH:10]=1
Reactant: O=C=O
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOc1cccs1
Agent: [Hg]
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOc1ccc(C(=O)O)s1
Temperature: 25 °C

Procedure:
When in Example 2, 1-bromo-3,7,11,15-tetramethyhexadecane is substituted for 1-bromohexadecane, 2-(3,7,11,15-tetramethylhexadecyloxy)thiophene is obtained. A solution of 38.1 g (0.1 mole) of 2-(3,7,11,15-tetramethylhexadecyloxy)-thiophene in 50 ml of anhydrous ether is added over a 4 hour period to 6.0 g of sodium amalgam in 100 ml of anhydrous ether at reflux temperature (36°-39° C) under slight nitrogen pressure. The mixture is refluxed an additional 2 hours, then cooled to room temperature are carbonated by adding freshly crushed dry ice after which 20 ml of ethanol is added dropwise followed by the addition of 50 ml of water. The aqueous solution is separated from the ether layer, filtered and acidified with hydrochloric acid to precipitate 5-(3,7,11,15-tetramethylhexadecyloxy)-2-thiophenecarboxylic acid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=O)[C:2]1=2.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O=[C:19]([CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]3[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:27][CH3:28])[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)[C:2]1=2
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=Cc1cccc2c1OCC2
Product: CCCC1=C(C(=O)OCC)C(c2cccc3c2OCC3)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2,3-dihydobenzo[b]furan-7-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:20])[CH3:19]>>[ClH:1].[ClH:1].[CH:15]([N:11]1[CH2:12][CH2:13][CH2:14][N:8]([C:5]2[N:6]=[N:7][C:2]([C:25]3[CH:26]=[CH:27][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)([CH3:17])[CH3:16]
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: CC(C)N1CCCN(c2ccc(Cl)nn2)CC1
Product: CC(=O)Nc1ccc(-c2ccc(N3CCCN(C(C)C)CC3)nn2)cc1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1-(6-chloro-pyridazin-3-yl)-4-isopropyl-perhydro-1,4-diazepine and 4-acetamidophenylboronic acid. 1H NMR (400 MHz, CD3OD) δ 8.43 (d, 1H), 8.03 (d, 1H), 7.94 (m, 2H), 7.84 (m, 2H), 4.36 (m, 1H), 4.17 (m, 1H), 4.03 (m, 1H), 3.73 (m, 4H), 3.42 (m, 2H), 2.50 (m, 1H), 2.39 (m, 1H), 2.17 (s, 3H), 1.41 (d, 6H).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:25][CH2:26][CH2:27][CH2:28]Br)[CH2:9][CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:25][CH2:26][CH2:27][CH2:28][N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7])[CH2:9][CH3:10]
Reactant: CCCc1c(OCCCBr)ccc2c(CC(C)(C)C)noc12
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCN2C(=O)CCC2=O)ccc2c(CC(C)(C)C)noc12
Reaction time: 18 h

Procedure:
Pyrrolidine-2,5-dione (17 mg, 0.172 mmol) and 7-propyl-3-neopentyl-6-(3-bromopropyloxy)-1,2-benzisoxazole, from Example 9 above, (42 mg, 0.114 mmol) were combined in DMF (7 ml) with Cs2CO3 (56 mg, 0.17 mmol) at room temperature. The mixture was stirred 18 hours. The mixture was diluted with 2 ml H2O and acidified with TFA. The resulting mixture was purified by elution from a RP-18 reversed phase HPLC column with a 90:10 to 0:100 H2O:CH3CN gradient to yield 1-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[C:9]([CH3:15])[C:8]=1[CH3:16].[CH3:17][C:18](=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)CO.[C:28](=O)(O)[O-].[Na+]>ClCCl>[NH2:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:28])[C:10]2[O:14][C:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH3:17])[CH2:15][C:9]=2[C:8]=1[CH3:16]
Reactant: O=C([O-])O
Reactant: CC(=Cc1ccccc1)CO
Reactant: Cc1cc(O)c(C)c(C)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(Cc1ccccc1)O2
Yield: 19.3 %

Procedure:
Sulfuric acid (15 ml) was added to a solution of 4-amino-2,3,5-trimethylphenol (20.0 g, 0.13 mol) and 2-methyl-3-phenyl-2-propenol (25.0 g, 0.17 mol) in dichloromethane (100 ml) and the mixture was heated under reflux for 1 hour. The resulting reaction mixture was neutralized with aqueous saturated sodium bicarbonate solution and the product was extracted with ethyl acetate. The extract was washed with water and dried and then the solvent was distilled off. The residue was purified by silica gel column chromatography (isopropyl ether) and crystallized from hexane to obtain the desired compound (7.2 g, yield: 19.3% ) , m.p. 68°-69° C.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:44]1[CH:45]=[C:46]([C:51]2[CH:63]=[CH:62][C:54]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[CH:53][C:52]=2[CH3:64])[CH:47]=[N:48][C:49]=1[CH3:50].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd](Cl)Cl.O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:44]4[CH:45]=[C:46]([C:51]5[CH:63]=[CH:62][C:54]([C:55]([O:57][C:58]([CH3:60])([CH3:61])[CH3:59])=[O:56])=[CH:53][C:52]=5[CH3:64])[CH:47]=[N:48][C:49]=4[CH3:50])=[CH:24][N:23]=[C:22]([N:35]4[CH2:36][CH:37]([F:39])[CH2:38]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:4]=[C:3]([C:2]([F:42])([F:41])[F:1])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)C2)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1cnc(C)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1cnc(C)c(-c2cnc(N3CC(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
To a 10 mL microwave tube was added (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2-(3-fluoroazetidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 22, 86 mg, 0.142 mmol), tert-butyl 4-(5-chloro-6-methylpyridin-3-yl)-3-methylbenzoate (INTERMEDIATE 39, 41 mg, 0.129 mmol), potassium phosphate (41 mg, 0.194 mmol), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (XPHOS Biphenyl Precatalyst) (20.3 mg, 0.026 mmol), followed by dioxane (2 mL) and water (0.1 mL). The tube was sealed and stirred at 180° C. in the microwave reactor for 10 minutes. After cooling down, the solvent was evaporated. The residue was purified by silica gel chromatography (0 to 100% Ethyl acetate/hexane) and afforded the title compound as a white solid in 46% yield. LCMS (M+H)+: 760.2.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH:12]2[CH2:14][CH2:13]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.O.[OH:16][N:17]1[C:21]2C=CC=CC=2N=N1.[CH2:26](N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([O:11][CH:12]2[CH2:14][CH2:13]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:17]([O:16][CH3:26])[CH3:21])=[O:6]
Reactant: CCN(CC)CC
Reactant: On1nnc2ccccc21
Reactant: Nc1c(OC2CC2)cccc1C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(OC2CC2)c1N
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
In a flask at room temperature, was added 2-amino-3-cyclopropoxybenzoic acid (6.61 g, 34.2 mmol) N,O-dimethylhydroxylamine hydrochloride (10.01 g, 103 mmol), N-ethyl-N″-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.87 g, 41.1 mmol) and 1-hydroxybenzotriazole hydrate (6.29 g, 41.1 mmol) in 50 ml of DMF. To the solution was added triethylamine (19.07 mL, 137 mmol). The reaction solution was stirred at 60° C. overnight and then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate and transferred to a separatory funnel and washed with 10% LiCl, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide dark oil. The crude product mixture was purified via ISCO (0%-50% of EtOAC/DCM in 15 minutes, 120 g column) to give 2-amino-3-cyclopropoxy-N-methoxy-N-methylbenzamide (5.2 g, 22.01 mmol, 64.3% yield). HPLC: RT=1.975 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=237.12 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.17 (dd, J=8.0, 1.2 Hz, 1H), 7.02 (dd, J=7.9, 1.3 Hz, 1H), 6.67 (t, J=7.9 Hz, 1H), 4.78 (br. s., 2H), 3.88-3.73 (m, 1H), 3.69-3.56 (m, 3H), 3.36 (s, 3H), 0.92-0.72 (m, 4H)).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[NH:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.[O:17]1[CH2:41][CH:18]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH:38]3[O:40][CH2:39]3)=[CH:32][CH:31]=2)([CH3:29])[CH3:28])=[CH:23][CH:22]=1.[OH-:42].[K+]>C(O)C>[OH:17][CH:18]([CH2:41][N:6]1[C:5](=[O:42])[C:4]2([CH2:3][C:2]([CH3:1])([CH3:16])[NH:13][C:12]([CH3:15])([CH3:14])[CH2:11]2)[NH:8][C:7]1=[O:9])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH:38]([OH:40])[CH2:39][N:6]3[C:5](=[O:10])[C:4]4([CH2:3][C:2]([CH3:16])([CH3:1])[NH:13][C:12]([CH3:15])([CH3:14])[CH2:11]4)[NH:8][C:7]3=[O:9])=[CH:34][CH:35]=2)([CH3:29])[CH3:28])=[CH:25][CH:26]=1
Reactant: [OH-]
Reactant: CC1(C)CC2(CC(C)(C)N1)NC(=O)NC2=O
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Agent: [K+]
Solvent: CCO
Product: CC1(C)CC2(CC(C)(C)N1)NC(=O)N(CC(O)COc1ccc(C(C)(C)c3ccc(OCC(O)CN4C(=O)NC5(CC(C)(C)NC(C)(C)C5)C4=O)cc3)cc1)C2=O

Procedure:
24.0 g of 7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione, 17.0 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane and 0.5 g of potassium hydroxide were reacted in 400 ml of 50% v/v aqueous ethanol, following the procedure described in Example 1. The desired Compound No. 1 was obtained in the form of crystals melting at 117°-119° C.
Reaction SMILES: [H-].[Na+].[CH2:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+:12].O.[CH3:14][N:15]([CH:17]=[O:18])C>>[CH2:3]([N:15]1[CH:14]=[CH:3][C:4]2[C:5](=[CH:6][N:12]=[CH:8][CH:9]=2)[C:17]1=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCc1ccccc1
Reactant: [NH4+]
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=c1c2cnccc2ccn1Cc1ccccc1
Temperature: 0 °C
Yield: 89 %

Procedure:
2H-[2,7]naphtyridine-1-on (200 mg, 1.368 mmol) was suspended in 6 mL of anhydrous DMF, and added with NaH (60% dispersion in mineral oil, 82 mg, 2.053 mmol) while stirring it at 0° C. under the nitrogen atmosphere. The mixture was cooled down at room temperature for about 2 hours, dropwisely added with benzyl chloride (0.19 mL, 1.642 mmol) at 0° C. and then stirred at room temperature for about 2 hours. The mixture was added with 5 mL of a saturated solution of ammonium chloride and 5 mL of distilled water, while stirring it at 0° C., and extracted twice with 30 mL of EtOAc. The resulting organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous sodium sulfate, filtered and then concentrated. A silica gel column chromatography (5% MeOH/MC) was performed on thus obtained concentrated residue and obtained 288 mg (89%) of 2-benzyl-2H-[2,7]naphtyridine-1-on in white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[Cl:10][C:11]1[CH:16]=[C:15]([N:17]=[C:18]=S)[CH:14]=[C:13]([Cl:20])[CH:12]=1.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:31][NH2:32]>C1COCC1.O.C(O)(=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([NH:17][C:18]2[C:7]3[CH2:8][C:2]4[S:1][CH:5]=[CH:4][C:3]=4[C:6]=3[NH:32][N:31]=2)[CH:14]=[C:13]([Cl:20])[CH:12]=1
Reactant: O=C1CCc2sccc21
Reactant: NN
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Clc1cc(Cl)cc(Nc2n[nH]c3c2Cc2sccc2-3)c1
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1,3-Dichloro-5-isothiocyanato-benzene (1.2 g, 7.4 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (3,5-Dichloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine as brown solid in 30% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[O:7][N:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:45][C:46]1[CH:47]=[C:48]([CH:62]=[CH:63][CH:64]=1)[CH2:49][NH:50][C:51]([NH:53][C:54]1[S:55][CH:56]=[C:57]([CH2:59][NH:60][CH3:61])[N:58]=1)=[O:52]>CN(C)C=O.O>[F:45][C:46]1[CH:47]=[C:48]([CH:62]=[CH:63][CH:64]=1)[CH2:49][NH:50][C:51](=[O:52])[NH:53][C:54]1[S:55][CH:56]=[C:57]([CH2:59][N:60]([CH3:61])[C:10]([C:9]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][O:7][C:8]=2[CH3:13])=[O:12])[N:58]=1
Reactant: COC(=O)c1noc(C)c1C(=O)O
Reactant: CNCc1csc(NC(=O)NCc2cccc(F)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1noc(C)c1C(=O)N(C)Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-(methoxycarbonyl)-5-methylisoxazole-4-carboxylic acid (1 mmol) was dissolved in N,N-dimethylformamide (5 ml), then diisopropylethylamine (1.2 eq.) and TBTU (1.2 eq) was added and stirred at room temperature for 5 minutes. 1-(3-fluorobenzyl)-3-(4-((methylamino)methyl)thiazol-2-yl)urea (1.0 mmol) was added and stirred overnight. Water (20 ml) was added to the reaction. The precipitate was filtered, washed with water and dried. The crude was purified by column using 0-100% gradient of 10% MeOH/EtOAc and hexanes to afford methyl 4-(((2-(3-(3-fluorobenzyl)ureido)thiazol-4-yl)methyl)(methyl)carbamoyl)-5-methylisoxazole-3-carboxylate.
Reaction SMILES: [C:1](=[O:3])=[O:2].O[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=CC=2)(C)C)=CC=1.C(C1C=CC([OH:36])=CC=1)(C1C=CC=CC=1)(C)C.[Na][Na].C(Cl)(Cl)=O>C(Cl)Cl.C(N(CC)CC)C>[C:17]([OH:20])(=[O:36])[CH2:18][CH2:19][CH2:14][CH2:11][CH2:8][CH2:9][CH2:10][CH2:5][C:1]([OH:3])=[O:2]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=C=O
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Agent: O=C(Cl)Cl
Agent: [Na][Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCCCCCCC(=O)O

Procedure:
A 2000 mL five neck Morton flask equipped with a bottom outlet was fitted with a mechanical stirrer, a pH probe, an aqueous sodium hydroxyde (50%) inlet tube, a Claisen adapter to which dry ice condenser was attached, and a gas inlet tube. The flask was charged with bisphenol A (71 g, 311 retool), triethylamine (0.9 mL), p-cumylphenol (2.0 g, 9 retool), methylene chloride (220 mL), and the disodium salt solution of DDDA described above. Then phosgene was introduced at a rate of 2 g/rain, while the pH was maintained at 8 by addition of caustic for 10 minutes; the pH was then raised and maintained at around 10.5 while phosgene addition continued for 10 additional minutes. The total amount of phosgene added was 40 g (400 mmol). The pH was adjusted to 11-11.5 and the organic phase was separated from the brine layer and washed with 2% hydrochloric acid (3×300 mL), and with deionized water (5×300 mL).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[C:4]=2[CH:3]=1
Reactant: Cc1ccc(Br)nc1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2c(-c3cnn(C)c3)cc3cnc(Br)cc32)nc1
Temperature: 210 °C
Yield: 46.6 %

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 84 mg 0.303 mmole) and 2-bromo-5-methylpyridine (78 mg, 0.45 mmole) were dissolved in DMA (2.1 ml) and potassium carbonate (60 mg, 0.42 mmole) and copper(I) iodide (12 mg, 0.066 mmole) were added. The reaction was placed under argon and heated by microwave at 210° C. for 60 minutes. Further 2-bromo-5-methylpyridine (49 mg) and potassium carbonate (40 mg) were added and the reaction again heated at 210° C. under microwave irradiation for 60 minutes. The reaction was taken up in ethyl acetate (30 mL) and the solution washed with water (3×10 mL) and brine. The aqueous was filtered through Celite and backwashed with ethyl acetate (10 mL). The combined organic layers were dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with ethyl acetate to afford the title compound 52 mg (46%). 1H-NMR (CDCl3, 500 MHz): 2.48 (s, 3H), 3.88 (s, 3H), 6.70 (d, J=0.95 Hz, 1H), 7.09 (d, J=7.88 Hz, 1H), 7.24 (m, 1H), 7.25 (s, 1H), 7.44 (t, J=0.95 Hz, 1H), 7.66 (m, 1H), 8.53 (m, 1H), 8.65 (d, J=0.95 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:3]=1.[I-].[K+].CCN(C(C)C)C(C)C.[NH:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1>CN(C=O)C.O>[NH:29]1[CH:33]=[CH:32][C:31]([NH:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:3]=2)=[N:30]1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)c1nc(Cl)c2ccc(I)cc2n1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc(Nc2cc[nH]n2)c2ccc(I)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of ethyl 4-chloro-7-iodoquinazoline-2-carboxylate (0.138 g, 0.38 mmol) in DMF (2 mL) at rt under argon were added potassium iodide (0.069 g, 0.42 mmol), DIEA (0.079 mL, 0.45 mmol), and 1H-pyrazol-3-amine (0.038 g, 0.46 mmol). The mixture was stirred at rt overnight then diluted with H2O (15 mL). The precipitate was collected by filtration, washed with H2O, and dried under high vacuum for several hours to afford ethyl 4-(1H-pyrazol-3-ylamino)-7-iodoquinazoline-2-carboxylate as a yellow solid (0.130 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ1.34 (t, 3H), 4.38 (q, 2H), 7.14 (m, 1H), 7.72 (m, 1H), 7.94 (d, 1H), 8.28 (d, 1H), 8.48 (d, 1H), 10.92 (s, 1H), 12.58 (s, 1H); LC-MS (ESI) m/z 410 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].[H][H].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>CS(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([OH:7])=[O:6])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: [H][H]
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O)c1cc(O)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)c1cc(OCC(=O)c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 206 mg. (1 m mole) of 3-hydroxy-5-trifluoromethylbenzoic acid dissolved in 2.5 ml. of dimethylsulfoxide is added 85 mg. (2 m moles) of a 56.6% sodium hydride suspension in oil. When the hydrogen evolution has ceased, 199 mg. (1 m mole) of α-bromoacetophenone is added and the reaction mixture is allowed to stir at room temperature for 2 hours. The reaction is diluted with 10 ml. of water and extracted with ether. The aqueous phase is acidified and the product extracted with ether. Removal of the ether under reduced pressure followed by sublimation at 150° C. and 0.1 mm pressure provided the pure product, m.p. 180°-182° C.